DSG1 – Severe Dermatitis, Multiple Allergies and Metabolic Wasting Syndrome

Biallelic loss‑of‑function mutations in DSG1 have been robustly associated with a severe multisystem disorder characterized by striking cutaneous and systemic manifestations. This syndrome, often referred to as SAM syndrome, encompasses severe dermatitis, multiple allergies, and metabolic wasting. Multiple independent studies, including those reporting families from consanguineous backgrounds, have demonstrated that homozygous or compound heterozygous mutations in DSG1 lead to a profound disruption in desmosomal integrity and epidermal barrier function (PMID:25041099). The evidence thus far has come from well‐documented case reports and familial segregation studies, which consistently show that these mutations cause mRNA decay and complete loss of DSG1 protein expression.

The clinical genetic evidence is supported by the identification of diverse variant types ranging from nonsense to frameshift mutations that disrupt the coding sequence. For example, the variant c.2659C>T (p.Arg887Ter) has been reported in a patient from a third independent family, confirming the recurrence and pathogenicity of loss‑of‑function alleles (PMID:25041099). In addition, additional affected relatives in these families provide further segregation evidence, strengthening the gene–disease correlation.

Functional studies complement the genetic findings by demonstrating that DSG1 deficiency leads to impaired desmosomal adhesion and epidermal structure. In vitro assays have shown that the absence of DSG1 results in significant mRNA decay and loss of protein function, which in turn compromises cell–cell adhesion and epidermal integrity (PMID:30943110). Moreover, experimental models have confirmed that reduced desmosomal contacts correlate with the clinical phenotype observed in SAM syndrome.

The integration of multi‐patient studies and functional assessments provides a coherent narrative that links the genetic alterations in DSG1 with the clinical manifestations of SAM syndrome. The combined evidence from genetic case reports, segregation analysis, and functional experiments exceeds the traditional ClinGen scoring maximum, reinforcing a strong association between DSG1 mutations and this syndrome.

Key take‐home: The compelling convergence of genetic and functional evidence confirms that DSG1 mutations are strongly associated with severe dermatitis, multiple allergies, and metabolic wasting syndrome, making this finding critically important for diagnostic decision‑making and potential therapeutic interventions.

References

• The British journal of dermatology • 2015 • Loss of desmoglein 1 associated with palmoplantar keratoderma, dermatitis and multiple allergies PMID:25041099
• Pediatric dermatology • 2024 • SAM Syndrome Presenting With Pulmonary Stenosis: A Case Report and Literature Review PMID:39644136
• Nature genetics • 2013 • Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting PMID:23974871
• Molecular biology of the cell • 2019 • The desmosome is a mesoscale lipid raft‐like membrane domain PMID:30943110

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